Atovaquone is chemically described as trans 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone and has the following structure of formula 1:

Atovaquone is an antiprotozoal agent and is useful in the treatment of Pneumocystis carinii, Pneumocystis pneumonia, Plasmodia, tachyzoite and cyst forms of Toxoplasma gondii and Malaria in combination with proguanil. Atovaquone is the active ingredient in two drugs, the first is an oral suspension (750 mg/5 mL) under the trade name Mepron® and is indicated for the treatment and prophylaxis of Pneumocystis carinii infection and the second drug is a combination with proguanil hydrochloride, under the brand name Malarone® tablets for the prophylaxis of Malaria. U.S. Pat. Nos. 4,981,874 and 5,053,432 describe Atovaquone and a pharmaceutical composition thereof and exemplify the crystallization of Atovaquone in acetonitrile.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal lattice. Thus, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although these differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray powder diffraction (XRPD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
U.S. Publication No. 2009/0105350 describes a process for the preparation of Atovaquone polymorph III characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees 20±0.2° 0) at about 7.0, 9.7, 14.2, 14.8, 17.0, 19.2, 20.4, 22.1, 22.7, 26.9 and 28.7. According to this publication, Atovaquone is dissolved in an aprotic polar solvent followed by the addition of a suitable antisolvent in order to precipitate and isolate Atovaquone polymorph III.
U.S. Publication No. 2010/0152302 discloses a crystallization process of Atovaquone using acetonitrile as a solvent, in order to obtain two polymorphic forms of Atovaquone, one of which, designated as “Form A”, exhibited characteristic peaks (expressed in degrees 20±0.2° 0) at about 7.3, 10.0, 14.4, 15.1, 17.0, 18.8, 20.4, 22.2, 23.6, and 24.6. Form A was further characterized by Differential Scanning calorimetry (DSC) thermogram showing characteristic sharp endotherm at 221° C. The process for the preparation of Atovaquone “Form A” described in this publication, comprises treating Atovaquone with acetonitrile followed by cooling to a temperature of between about 0° C.-30° C. and isolating the obtained product.
The preparation of stable polymorphic forms of Atovaquone has the drawback of being expensive, time consuming, complicated and inappropriate to large scale manufacturing.
There remains a need to provide an alternative process for making Atovaquone which is cost-effective, feasible and highly reproducible on industrial scale to yield a stable polymorphic form on a consistent basis.